Liver involvement by cancer occurs frequently and is a major source of morbidity and mortality. Systemic chemotherapy for liver cancer has been relatively ineffective whereas there are indications that regional infusions have great potential. Accordingly, the overall aim of this proposal is the development of pharmacologically rational hepatic arterial drug infusions. There are several aspects to our approach, the first being pharmacokinetic studies to define whether hepatic arterial infusion selectively increases tumor exposure to drug and thereby exploits the usual steep dose response curve. Such studies will attempt to define for dichloromethotrexate (DCMTX) and mitomycin C (Mito) the best schedule to achieve maximum hepatic drug exposure with minimal systemic exposure. The second aspect of our proposal is the development and evaluation of a totally implanted system for continuous hepatic arterial drug infusions in ambulatory outpatients. Non-thrombogenic silastic catheters will be surgically implanted with Tc-99m microsphere nuclide angiography to assure adequate drug distribution to the tumor-bearing liver at low infusion rates. A titanium infusion pump is implanted subcutaneously and attached to the catheter for continuous infusion. A side-port on the pump allows direct catheter injections for short term or pulse drug administration as well as for nuclide angiography. This totally implanted system will be used for a phase II evaluation of fluorodeoxyuridine (FUdR), DCMTX, Mito, and bischlorethylnitrosourea (BCNU) tested in sequence in order to define cross-resistance. Thereafter, phase I-II studies of non-cross-resistant combinations of the cycle-non-specific and cycle-specific agents in this group will be initiated (potential combinations are Mito/FUdR, Mito/DCMTX, BCNU/FUdR, and BCNU/DCMTX). Thorough evaluation of this drug delivery system and these selected antineoplastic agents should have broad impact on cancer chemotherapy and clinical pharmacology.